Piperidine derivatives and anti-platelet agents containing the same

ABSTRACT

The present invention relates to a novel serotonin antagonist and an anti-platelet agent, more particularly, a serotonin antagonist and an anti-platelet agent which potently and specifically inhibit the serotonin 2 receptor with low adverse side effect.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates to a novel serotonin antagonist andan anti-platelet agent, more particularly, a serotonin antagonist and ananti-platelet agent which potently and specifically inhibit theserotonin 2 receptor with low adverse side effect.

[0003] 2. Discussion of the Background

[0004] It is believed that the thrombus greatly participates in ischemicdisorders such as cardiac infarction and cerebral infarction and, inparticular, the platelet plays an important role in the formation of thearterial thrombus. Known anti-platelet agents include arachidonic acidmetabolism-inhibiting agents, platelet cyclic nucleoside-related agents,thromboxane receptor antagonists. Aspirin and ticlopidine have also beenclinically used. However, the effect of these agents is not sufficientand thus development-of more effective agents has been in demand.

[0005] It is known that serotonin (5HT), which is stored in a granulesof the platelet, is released by activation of the platelet caused byvarious stimulations, and the released serotonin increases the calciumion level in the cell via the serotonin 2 (5HT₂) receptor on theplatelet membrane, resulting in aggregation of the platelet. It isbelieved that the 5HT₂ receptor existing in the vascular smooth muscleparticipates in the blood vessel contraction. Accordingly, the 5HT₂receptor antagonist is expected to have vasoconstriction inhibitingactivity in addition to the platelet aggregation inhibiting activityand, therefore, may also have potent anti-thrombus function.

SUMMARY OF THE INVENTION

[0006] Accordingly, one object of this invention is to provide a novelserotonin antagonist and an anti-platelet agent which potently andspecifically inhibit the serotonin 2 receptor with low adverse sideeffect.

[0007] This and objects which will become apparent hereinafter have beenachieved with the following novel serotonin agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] The present invention relates to a serotonin antagonist or ananti-platelet agent which comprises as an active ingredient a piperidinederivative represented by the following general formula (I):

[0009] wherein

[0010] A¹ represents an unsubstituted or substituted pyridyl, piperidyl,piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino orpiperazinyl group, a substituted alkyl group having from 1 to 8 carbonatoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms,or an unsubstituted or substituted alkoxyl group having 1 to 8 carbonatoms,

[0011] X¹ represents a hydrogen atom or a halogen atom selected from thegroup consisting of bromine, chlorine, flourine and iodine,

[0012] Y¹represents one of the following organic groups:

[0013] —CONH—, —NHCO—, —CONHCH₂—, —(CH₂)_(n)— or —COO—,

[0014] wherein n is an integer of from 0 to 4, and

[0015] Z¹ represents one of the following organic groups:

[0016] —CH═CH—, —S—CH₂—, —S— or —CH₂—CH₂—,

[0017] or a salt thereof.

[0018] Preferred substituents for A¹ in the above general formula (I)include:

[0019] R¹—CO—and

[0020] wherein

[0021] R¹ is a hydrogen atom, an alkyl or alkoxyl group having from 1 to6 carbon atoms, an amino group which may be substituted by an alkylgroup having from 1 to 6 carbon atoms, or an acylaminoalkyl group havingfrom 1 to 6 carbon atoms, and R² and R³, which may be the same ordifferent, each represents a hydrogen atom, an alkyl, acyl oralkoxycarbonyl group having from 1 to 6 carbon atoms, or anaminocarbonyl group which may be substituted by an alkyl group havingfrom 1 to 6 carbon atoms.

[0022] Illustrative examples of such preferred substituents of A¹include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl, N-acetyl-N-alanyl,N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl,N-ethyl-N-formyl and N-ethyl-N-acetyl.

[0023] Preferred examples of Y¹ in the general formula (I) include agroup —CONH—.

[0024] Preferred examples of Z¹ include —CH═CH—.

[0025] Among the compounds represented by the general formula (I), thecompounds represented by the following general formula (II) are novelcompounds.

[0026] wherein

[0027] A² represents an unsubstituted or substituted piperidyl,piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino orpiperazinyl group, a substituted alkyl group having from 1 to 8 carbonatoms, a substituted cycloalkyl group having from 4 to 8 carbon atoms,or an unsubstituted or substituted alkoxyl group having 1 to 8 carbonatoms.

[0028] When A² has a substituent, the substituent is one of thefollowing groups.

[0029] R⁴—CO—

[0030] wherein

[0031] R⁴ represents an alkyl or alkoxyl group having from 1 to 6 carbonatoms, an amino group which may be substituted by an alkyl group, or anacylaminoalkyl group, and

[0032] R⁵ and R⁶, which may be the same or different, each represents ahydrogen atom, an alkyl, acyl or alkoxycarbonyl group having from 1 to 6carbon atoms, or an aminocarbonyl group which may be substituted by analkyl group, and

[0033] X², Y², and Z², respectively, have the same meanings as X¹, Y¹,and Z¹.

[0034] Preferred substituents for A² include acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl,N-acetyl-β-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl,N-methyl-N-propionyl, N-ethyl-N-formyl, N-ethyl-N-acetyl, and the like.

[0035] Preferably, Y² is a group —CONH—.

[0036] Preferably, Z² is a group —CH═CH—.

[0037] The piperidine derivative represented by the above generalformula (I) may be prepared by the conventional method, for example, bythe method described in an unexamined published Japanese patentapplication 3-47168, incorporated herein by reference.

[0038] For example, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene-1-(2-t-butoxycarbonylamino)ethyl)piperidine(compound (3)) included in the general formula (I) can be easilyobtained by subjecting N-t-butoxycarbonyl-2-bromoethylamine (compound(1)) and 4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)piperidine (compound(2)) to the condensation reaction in the presence of a base such astriethylamine, as shown in the Reaction Scheme

[0039] Similarly, 1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide (compound(6)) included in the general formula (I) can be easily obtained bysubjecting the compound 4, which is obtained by removing at-butoxycarbonyl group from the compound 3 using 4 M hydrochloricacid/dioxane, etc., and 1-formylisonipecotic acid (compound (5)) to thecondensation reaction using a condensation agent such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, as shown in the ReactionScheme II.

[0040] The reaction product obtained by these production methods isisolated and purified as a free compound or a salt thereof. Isolationand purification may be carried out by extraction, concentration,evaporation, crystallization, and various types of chromatography.

[0041] Examples of the salt of the piperidine derivative include acidaddition salts with inorganic acid such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid andwith organic acids such as formic acid, acetic acid, lactic acid,salicylic acid, mandelic acid, citric acid, oxalic acid, maleic acid,fumaric acid, tartaric acid, tannic acid, malic acid, p-toluenesulfonicacid, methanesulfonic acid, and benzenesulfonic acid.

[0042] The piperidine derivative represented by the general formula (I)exhibits a serotonin antagonizing activity and is useful as an agent forthe treatment of ischemic disorders, thrombosis, obstruction, mentaldiseases (depression, anxiety), diabetic complication, arteriosclerosis,hypertension, arrhythmia, migraine, microcirculation failure, and thelike. In particular, as an anti-platelet agent, the piperidinederivative represented by the general formula (I) is useful as an agentfor the treatment of various ischemic disorders, thrombosis,obstruction, angiitis, diabetic complication, arteriosclerosis,nephropathy, and ulcer, pain, rhigosis, etc. due to chronic arterialobstruction, and also can be used as a treating agent for improvingvarious ischemia accompanying circulation failure, for preventingrestenosis after surgical treatment of ischemic heart diseases, and forimproving blood circulation.

[0043] When the piperidine derivative of the general formula (I) is usedas a serotonin antagonist or an anti-platelet agent, the administrationroute may be either oral or parenteral. Though the clinical dose maydiffer depending on the age, body weight, and condition of the patientand on the administration method, but the dose per an adult per day isgenerally from 0.01 mg to 500 preferably from 0.1 mg to 50 mg in thecase of oral administration and 1 μg to 100 mg preferably from 0.01 mgto 10 mg in the case of parenteral administration.

[0044] As the dosage form, usual dosage forms such as tablets, powders,sugar-coated preparations, capsules and solutions may be employed andsuch dosage forms can be prepared by the conventional method making useof usual pharmaceutical adjuvants.

[0045] This application is based on Japanese Patent Application No.081499/1944, the text of which is incorporated herein by reference.

EXAMPLES

[0046] Having generally described this invention, a furtherunderstanding can be obtained by reference to certain specific exampleswhich are provided herein for purposes of illustration only and are notintended to be limiting unless otherwise specified.

Preparation Procedure A Synthesis of1-methoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethylisonipecotamidehydrochloride Step 1 Synthesis of 2-t-Butoxycarbonylaminoethylbromide

[0047] 2-Aminoethylbromide hydrobromide (35.77 g, 174.6 mmol) anddi-t-butyl dicarbonate (22.80 g, 104.5 mmol) were added to a mixedsolvent of 300 ml of diethyl ether and 300 ml of water. Then, sodiumhydrogencarbonate (44.00 g, 523.7 mmol) was gradually added and themixture was stirred at room temperature overnight. The diethyl etherlayer was washed with 80 ml of 1N hydrochloric acid and then with 80 mlof a saturated aqueous sodium chloride solution, and dried overmagnesium sulfate powder. The solvent was evaporated to obtain thetitled compound

[0048] Amount obtained: 21.57 g (96.25 mmol); Yield: 92%

Step 2 Synthesis of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-t-butoxycarbonylamino)ethyl)piperidine

[0049] 2-t-Butoxycarbonylaminoethylbromide (4.5 g, 20.1 mmol),4(5H-dibenzo[a,d] cyclohepten-5-ylidene)piperidine (2.7 g, 10.0 mmol),and triethylamine (4.2 ml, 30 mmol) were added to acetonitrile (300 ml),and the mixture was stirred on an oil bath at 50° C. for 16 hours. Thetemperature was lowered to room temperature, the solvent was evaporated,and the residue was dissolved in 300 ml of ethyl acetate. After removinginsoluble matters by filtration, the filtrate was washed with 100 ml of1N hydrochloric acid, 100 ml of a 1N aqueous sodium hydroxide solution,and 100 ml of a saturated sodium chloride aqueous solution, and driedover magnesium sulfate powder. The solvent was evaporated and theresidue was purified by silica gel column chromatography to obtain thetitled compound.

[0050] Amount obtained: 3.6 g (8.6 mmol); Yield: 86%

Step 3 Synthesis of 1-(2-aminoethyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine dihydrochloride

[0051] 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-t-butoxycarbonylamino)ethyl)piperidine (8.47g, 20.4 mmol) was dissolved in 100 ml of dichloromethane, and 100 ml ofa 4N hydrochloric acid-dioxane solution was added thereto, followed bystirring at room temperature for 1 hour. The solvent was evaporated toobtain the titled compound (8.56 g).

Step 4 Synthesis of 1-t-butoxycarbonyl-N-(2-(4-(5H-dibenzo[a, d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide

[0052] 1-(2-Aminoethyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine dihydrochloride (2.3 g, 6.0 mmol),1-t-butoxycarbonylisonipecotic acid (1.6 g, 7.2 mmol), triethylamine(3.0 ml, 21.6 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (1.4 g, 7.2 mmol) were mixed, and the mixture was stirredat room temperature overnight. After evaporating the solvent, theresidue was dissolved in 100 ml of dichloromethane, washed with 100 mlof 1N hydrochloric acid, 100 ml of a 1N aqueous sodium hydroxidesolution, and 50 ml of a saturated aqueous sodium chloride solution. Thesolvent was evaporated and the residue was purified by silica gelchromatography to obtain the titled compound.

[0053] Amount obtained: 2.0 g (3.8 mmol); Yield: 63%

Step 5 Synthesis of N-(2-(4-(SH-dibenzo[a,d]cyclohepten-5-ylidene)1-piperidinyl))ethylisonipecotamidedihydrochloride

[0054] 10 ml of 4N hydrochloric acid-dioxane solution was added to1-t-butoxycarbonyl-N- (2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide (0.10 g,0.185 mmol), and the mixture was stirred at room temperature for 1 hour.The solvent was evaporated to obtain the titled compound.

[0055] Amount obtained: 0.093 g (0.186 mmol); Yield: 100%

Step 6 Synthesis of 1-methoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene-1-piperidinyl))ethylisonipecotamide hydrochloride

[0056] N-(2-(4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamidedihydrochloride (0.59 g, 1.18 mmol) and triethylamine (0.8 ml, 5.70mmol) were dissolved in 50 ml of dichloromethane, and methylchloroformate (0.1 ml, 1.40 mmol) was added. The mixture was stirred for1 hour and 100 ml of dichloromethane was added. The mixture was washedwith 70 ml of water, 70 ml of a 1N aqueous sodium hydroxide solution,and 70 ml of a saturated aqueous sodium chloride solution, and purifiedby silica gel chromatography. The product obtained was converted intothe hydrochloride form to give the titled compound. Amount obtained:0.39 g (0.75 mmol); Yield: 63%

[0057] The compounds shown in Table 1 were produced by the similarmanner as described in Preparation procedure A.

A Y X Z pKi pIC₅₀ 1

—CONH— H —CH═CH— 8.2 7.5 2

8.6 7.3 3

8.4 7.2 4

8.5 7.2 5

8.0 6.5 6

— 6.9 7

8.5 6.7 8

7.9 6.6 9

7.8 7.1 10

8.8 — 11

8.8 7.0 12

8.6 6.6 13

9.3 — 14

— — 15

— — 16 CH₃CH₂O— — 7.6 17 (CH₃)₃CO— — 7.0 18

8.9 7.3 19

8.3 6.4 20

8.0 6.3 21

7.8 6.5 22

8.2 5.8 23 H₂N(CH₂)₃— — 7.6 24 HCONH(CH2)₃— 9.8 7.2 25 CH₃CONH(CH₂)₃—9.2 6.6 26 (CH₃)₃COCONH(CH₂)₃— — 7.2 27 (CH₃)₂NCONH(CH₂)₃— 9.2 6.9 28CH₃NH(CH₂)₃— — 6.6 29 (CH₃)₃COCON(CH₂)₃—CH₃ — 7.1 30

—CONHCH₂— 8.3 6.4 31 (CH₃)₃CO— 8.8 — 32 H₂N— —CH₂— — — 33

—COO— 8.3 7.4 34 H₂N— — —CH₂—CH₂— — — 35 (CH₃)₃CO— —CONH— 8.3 — 36

8.9 5.8 37 H₂N— — —S— 8.4 5.0 38 (CH₃)₃CO— —CONH— 9.1 7.3 39

9.2 7.1 40

F —S—CH₂— 7.1 5.6

Preparation Procedure B Synthesis of 1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-Piperidinyl)butyl)morpholine Step 1 Synthesisof 1-(4-oxo-4-morpholinobutyryl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine

[0058] In 50 ml of dichloromethane, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (0.27 g, 1.0 mmol), succinic anhydride(0.12 g, 1.2 mmol), and triethylamine (0.17 ml, 1.2 mmol) were stirredat room temperature overnight. Morpholine (0.14 ml, 1.6 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.27 g, 1.4mmol) were added and the mixture was further stirred at room temperaturefor 8 hours. The reaction mixture was washed with 30 ml of 1Nhydrochloric acid, 30 ml of a 1N aqueous sodium hydroxide solution, and30 ml of a saturated aqueous sodium chloride solution, dried overmagnesium sulfate powder, and purified by silica gel chromatography toobtain the titled compound. Amount obtained: 0.44 g (1.0 mol); Yield:100%

Step 2 Synthesis of 1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)1-piperidinyl)butyl)morpholine dihydrochloride

[0059] In tetrahydrofuran (60 ml),1-(4-oxo-4-morpholinobutyryl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (0.44 g, of 1.00 mmol) was reacted withlithium aluminum hydride (0.38 g, 10.0 mol) at 0° C., and furthertreated in accordance with the conventional method to obtain the titledcompound. Amount obtained: 0.32 g (0.66 mmol); Yield: 66%

[0060] The compounds shown in Table 2 were produced by the similarmanner as described in Preparation procedure B.

A Y X Z pKi pIC₅₀ 41

—(CH₂)₂— H —CH═CH— 8.2 6.9 42

8.7 6.6 43

—(CH₂)₃— 7.3 — 44

—(CH₂)₂— —CH₂—CH₂— 7.9 — 45

—S— 8.1 —

Test Example 1

[0061] The binding affinity to the serotonin 2 receptor was evaluatedusing a bovine cerebral cortex membrane sample. To 200 μl of a bovinemembrane sample adjusted to 50 mg (wet weight) membrane/ml were added200 μl of 3 nM [³H]-ketanserin and 200 μl of a test compound solutionprepared by dissolving a test compound in 1.7% ethanol, followed bymixing. The mixture was incubated at 25° C. for 30 minutes and filteredwith a glass filter. The radioactivity trapped on the filter wasmeasured with a liquid scintillation counter. The non-specific bindingwas defined by 10⁻⁶ M LY53857. The concentration of the test compoundwhich inhibits 50% of the specific binding of [³H]-ketanserin (i.e.,IC₅₀ value) was obtained, and the Ki value was calculated in accordancewith the following equation. The results are shown as the negativelogarithm of the Ki value (i.e., pKi value).$K_{1} = \frac{{IC}_{50}}{1 + \frac{\lbrack L\rbrack}{K_{d}}}$

[0062] In the equation, Ki indicates the dissociation constant and [L]indicates the concentration of [³H]-ketanserin.

[0063] From the results in Tables 1 and 2, it is apparent that thepiperidine derivative of the present invention exhibits strong bindingaffinity to the serotonin 2 receptor.

Test Example 2

[0064] The anti-platelet effect due to the serotonin antagonisticactivity was measured in vitro using the platelet of SD rats (bodyweight: about 300 to 400 g, male). Platelet rich plasma (PRP) andplatelet poor plasma (PPP) were prepared from blood with 0.38% sodiumcitrate which was obtained from aorta abdominalis of a rat under diethylether anesthesia. The platelet concentration of PRP was adjusted to5×10⁸ platelets/ml by adding PPP. Then, the test compound dissolved in0.4% aqueous ethanol was added, and the mixture was incubated at 37° C.for 3 minutes. The platelet aggregation induced by addition of 0.5 μM or0.8 μM adenosine diphosphate (ADP)+ serotonin was measured as anincrease in optical transmittance of PRP. The concentration of the testcompound which inhibits 50% of the increase in platelet aggregationwhich is obtained with serotonin without a test compound was measured,and its negative logarithm (pIC₅₀) was calculated. The results are shownin the Table 1 and 2. From these results, it is apparent that thepiperidine compound of the present invention potently inhibits theplatelet aggregation by serotonin.

Test Example 3

[0065] The anti-platelet effect due to the serotonin antagonisticactivity was measured in vivo using SD rats (body weight: about 210 to330 g, male). The test compound was dissolved or suspended in arabic gumand orally administered to the rat in a dose shown in Table 3. Two hoursafter the administration of the test compound, the rat was anesthetizedwith diethyl ether and platelet rich plasma (PRP) and platelet poorplasma (PPP) were prepared from blood with 0.38% sodium citrate whichwas obtained from aorta abdominalis of the rat. The plateletconcentration of PRP was adjusted to 5×10⁸ platelets/ml by adding PPP.Then, the PRP was incubated at 37° C. for 3 minutes, and plateletaggregation induced by addition of 0.7 μM adenosine diphosphate (ADP)+serotonin was measured as an increase in optical transmittance of PRP.The aggregation occurred by addition of ADP alone and the maximumaggregation ratio by the simultaneous addition of ADP and serotonin weremeasured with respect to each group, and increase in aggregation causedby serotonin was calculated. The increase in aggregation caused byserotonin in the arabic gum administered group was taken as 100%, andthe effect of the test compound was judged using as an index theincrease in aggregation caused by the serotonin in the testcompound-administered group (n=3). The results are shown in the Table 3.Amount of Increase in aggregation administration by serotonin TestCompound (mg/kg) (%) arabic gum — 100 compound of No. 3 0.1 75.7 0.357.3 1 24.3 3 27 10 −2.7 compound of No. 9 0.3 57.3 compound of No. 170.3 50.7 compound of No. 18 0.3 94.9 compound of No. 38 0.3 82.4compound of No. 39 0.3 54.5 compound of No. 41 0.3 91.5

[0066] From the results in the Table 3, it is apparent that thepiperidine compound of the present invention potently inhibits theplatelet aggregation by serotonin even in the case of oraladministration.

Test Example 4

[0067] The serotonin antagonistic activity in the central nerve systemwas evaluated by measuring the inhibiting effect on head twitch of mouseinduced by 5-hydroxytryptophan (5HTP) A test compound in an amount of 1,3, 10, or 30 mg was respectively dissolved in 100 ml of water and, 90minutes before 5HTP administration, the solution (10 ml/kg body weight)was orally administered to a ICR mouse (body weight: 27 to 32 g, male)fasted from the previous day. As a control, 5% arabic gum was used.Carbidopa (6 mg/kg) was subcutaneously administered and, after 15minutes, 5HTP (180 mg/kg) was intraperitoneally administered. From the15 minutes after 5HTP administration, the number of head twitchesoccurred within 2 minutes were counted. The concentration of the testcompound which inhibits 50% of the number of head twitches in the 5%arabic gum administered group was obtained. The results are shown in theTable 4. TABLE 4 Test compound ID₅₀ (mg/kg) compound of No. 3 0.39cycloheptadine 0.12

[0068] From the results in the Table 4, it is apparent that thepiperidine compound of the present invention has low effect on thecentral nerve system and is a highly safe compound.

[0069] Having now fully described the invention, it will be apparent toone of ordinary skill in the art that many changes and modifications canbe made thereto without departing from the spirit or scope of theinvention as set forth herein.

What is claimed as new and is desired to be secured by Letters Patent ofthe United States is:
 1. A method of treating or preventing a diseasecaused by seretonin comprising administering effective amount of apiperidine derivative of general formula (I) or pharmaceuticallyacceptable salt thereof:

wherein A¹ represents an unsubstituted or substituted pyridyl,piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl,thiomorpholino or piperazinyl group, a substituted alkyl group havingfrom 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4to 8 carbon atoms, or an unsubstituted or substituted alkoxyl grouphaving 1 to 8 carbon atoms, X¹ is a hydrogen atom or a halogen atom, Y¹is —CONH—, —NHCO—, —CONHCH²—, —(CH₂)_(n)— or —COO—, wherein n is aninteger of from 0 to 4, and Z¹ is —CH═CH—, —S—CH₂—, —S— or —CH₂—CH₂—. 2.The composition of claim 1, wherein A¹ has a substituent and saidsubstituent is R¹—CO—

wherein R¹ is a hydrogen atom, an alkyl or alkoxyl group having from 1to 6 carbon atoms, an amino group which may be substituted by an alkylgroup having from 1 to 6 carbon atoms, or an acylaminoalkyl group havingfrom 1 to 6 carbon atoms, and R² and R³, which may be the same ordifferent, each represents a hydrogen atom, an alkyl, acyl oralkoxycarbonyl group having from 1 to 6 carbon atoms, or anaminocarbonyl group which may be substituted by an alkyl group havingfrom 1 to 6 carbon atoms.
 3. The method of claim 1, wherein saidsubstituent on A¹ is formyl, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl,N-ethylcarbamoyl, N-propylcarbamoyl, N,N-dimethylcarbamoyl,N,N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl,N-acetyl-β-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl,N-methyl-N-propionyl, N-ethyl-N-formyl or N-ethyl-N-acetyl.
 4. Themethod of claim 1, wherein Y¹ is a —CONH—.
 5. The method of claim 1,wherein Z¹ is a —CH═CH—.
 6. The method of claim 1, wherein thepiperidine derivative is 1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide.
 7. A methodof treating or preventing platelet aggregation comprising administeringan effective amount of a piperidine derivative of the formula (I) or asalt thereof or an active ingredient of a pharmaceutical composition:

wherein A¹ represents an unsubstituted or substituted pyridyl,piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl,thiomorpholino or piperazinyl group, a substituted alkyl group havingfrom 1 to 8 carbon atoms, a substituted cycloalkyl group having from 4to 8 carbon atoms, or an unsubstituted or substituted alkoxyl grouphaving 1 to 8 carbon atoms, X¹ is a hydrogen atom or a halogen atom, Y¹is —CONH—, —NHCO—, —CONHCH²—, —(CH₂)_(n)— or —COO—, wherein n is aninteger of from 0 to 4, and Z¹ is —CH═CH—, —S—CH₂—, —S— or —CH₂—CH₂—. 8.The method of claim 7, wherein the piperidine derivative is1-formyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide.
 9. Apiperidine derivative represented by the general formula (II) or a saltthereof:

wherein A² represents an unsubstituted or substituted piperidino,morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinylgroup, a substituted alkyl group having from 1 to 8 carbon atoms, asubstituted cycloalkyl group having from 4 to 8 carbon atoms, or anunsubstituted or substituted alkoxyl group having 1 to 8 carbon atoms,wherein suitable substituents include: R⁴—CO—

wherein R⁴ represents an alkyl or alkoxyl group having from 1 to 6carbon atoms, an amino group which may be substituted by an alkyl grouphaving from 1 to 6 carbon atoms, or an acylaminoalkyl group having from1 to 6 carbon atoms. R⁵ and R⁶, which may be the same or different, eachrepresents a hydrogen atom, an alkyl, acyl or alkoxycarbonyl grouphaving from 1 to 6 carbon atoms, or an aminocarbonyl group which may besubstituted by an alkyl group having from 1 to 6 carbon atoms, and X² isa hydrogen atom or a halogen atom, Y² is —CONH—, —NHCO—, —CONHCH²—,—(CH₂)_(n)— or —COO—, wherein n is an integer of from 0 to 4, and Z² is—CH═CH—, —S—CH₂—, —S— or —CH₂—CH₂—.
 10. The piperidine derivative ofclaim 9, wherein A² is substituted with a substituent selected from thegroup consisting of acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl,N-propylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl,N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl, N-acetyl-β-alanyl,N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl,N-ethyl-N-formyl and N-ethyl-N-acetyl.
 11. The piperidine derivative ofclaim 9, wherein Y² is a group —CONH—.
 12. The piperidine derivative ofclaim 9, wherein Z² is a group —CH═CH—.
 13. A compound selected from thegroup consisting of 1-methoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)1-piperidinyl))ethylisonipecotamide,N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,1-acetyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,1-t-butoxycarbonyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide,1-carbamoyl-N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,1-(N,N-dimethylcarbamoyl)-N-(2(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide,1-(N-acetylglycyl)-N-(2-(4(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1piperidinyl))ethylisonipecotamide,N-(2-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)piperidinyl))ethylpipecolamide, N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)) ethyl-(N-acetyl)pipecolamide,1-formyl-4-((2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylcarbamoyl)piperazine,N-(2-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-aminocyclohexanecarboxamide, N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-acetylaminocyclohexanecarboxamide, N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(1-t-butoxycarbonylamino)cyclohexanecarboxamide,4-5H-dibenzo[a,d]cyclohepten-5-ylidene))1-2-ethoxycarbonyl-amino)ethyl)piperidine,4-(5H-dibenzo[a,d]cyclohepten-5-ylidene-1-(2-t-butoxy-carbonylamino)ethyl)piperidine,N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(1-amino)cyclohexanecarboxamide,N-(2-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(1-acetylamino)cyclohexanecarboxamide, N-(2-(4-(5H-dibenzo [a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(1-t-butoxycarbonylamino)cyclohexanecarboxamide, N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(formylamino)cyclohexanecarboxamide,N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-1-(1-N,N-dimethylcarbamoylamino)cyclohexanecarboxamide, N-(2-(4-(5Hdibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-aminobutyramide,N-(2-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-piperidinyl))ethyl-4-formylaminobutyramide, N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-acetylaminobutyramide,N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-t-butoxycarbonylaminobutyramide,N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(N,N-dimethylcarbamoylamino)butyramide, N-(2(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(N-methylamino)butyramide,N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethyl-4-(N-methyl-t-butoxycarbonylamino)butyramide, 1-formyl-N-(3-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))propylisonipecotamide,4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-1(3-t-butoxycarbonylaminopropyl)piperidine, 1-(3-aminopropyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 1-formyl-isonipecotic acid2-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-1-piperidinyl)) ethylester, 1-(2-aminoethyl)-4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-t-butoxycarbonylamino)ethyl)piperidine,1-formyl-N-(2-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl))ethylisonipecotamide,1-(2-aminoethyl)-4-(9-thioxanthinidene)piperidine,4-(9-thioxanthinidene)-1-((2-t-butoxycarbonylamino)ethyl) piperidine,1-formyl-N-(2-(4-(9-thioxanthinidene)piperidinyl)) ethylisonipecotamide,1-formyl-N-(2(4-(11-H-dibenzo[b,e]thiepin-2-fluoro-11-ylidene)-1-piperidinyl))ethylisonipecotamide,1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)butyl)morpholine,1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5ylidene)-1-piperidinyl)butyl)thiomorpholine,1-(4-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)pentyl)morpholine,1-(4-(4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl)butyl)piperidine and1-(4-(4-(9-thioxanthilidene)piperidinyl)butyl)morpholine.